Within-host evolution of tandemly duplicated blaKPC-14 conferring cross-resistance to ceftazidime-avibactam, cefiderocol and aztreonam-avibactam in hypervirulent ST11 Klebsiella pneumoniae

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Objectives Hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKP) exhibiting cross-resistance to multiple antimicrobial agents represents a formidable therapeutic challenge. Therefore, elucidating the mechanisms driving antimicrobial resistance is crucial. Methods A ceftazidime-avibactam-resistant K. pneumoniae isolate was recovered and subjected to antimicrobial susceptibility testing and whole-genome sequencing. Resistance mechanisms were investigated through gene cloning and enzymatic kinetic assays. Public NCBI databases were interrogated to determine the prevalence of multicopy bla KPC genes. Growth curves and plasmid stability assays were performed to evaluate the fitness costs. Results An hv-CRKP isolate harboring two IS 26 -mediated copies of bla KPC-14 was identified following prolonged ceftazidime-avibactam therapy. The strain displayed high-level resistance to ceftazidime-avibactam, cefiderocol, and aztreonam-avibactam without appreciable fitness cost. Throughout treatment, the critically ill patient exhibited a persistently elevated estimated glomerular filtration rate. Comparative plasmid analysis demonstrated that IS 26 -mediated tandem duplication was widespread among plasmids carrying multiple copies of bla KPC . Conclusions Selective pressure from prolonged ceftazidime-avibactam therapy, with potential contributions from host-related factors affecting antimicrobial exposure, could facilitate the emergence of bla KPC variants and consequently promote cross-resistance. Dual-copy bla KPC substantially increased resistance levels without imposing a significant fitness burden. These findings underscore the value of timely genomic surveillance and antimicrobial susceptibility testing for optimizing antimicrobial therapy.

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